Transcript 36111

Menthol and Tobacco Smoke
Exposure:
What We Know; What We Don’t
And Where to Go
Second Conference on Menthol Cigarettes
Washington, DC
October 19 – 20, 2009
James R. Hébert, Sc.D., Health Sciences
Distinguished Professor of Epidemiology
Director, Cancer Prevention and Control
Principal Investigator, SCCDCN
South Carolina Statewide
Cancer Prevention & Control Program
Review of the Motivation for the 1st
Paper on Mentholated Cigarettes & CA
 In Western countries, conventional view is that 95%
of Squamous Cell Cancers of the Esophagus
(SCCE) are attributable to tobacco and alcohol
 Within the U.S., rates for Blacks are about 4 times
those of Whites, yet the use rates of tobacco and
alcohol are about equal
Also see:
1. Hebert JR. Differences in biological responses to cigarette smoking remain unexplained.
Am J Pub Health 1991; 81:1679-1680.
2. Hebert JR, Kabat GC. Menthol cigarette smoking and oesophageal cancer: Results of a
case-control study. Int J Epidemiol 1989; 18:37-44.
Menthol Cigarette Sales and Age-Adjusted
Esophageal Cancer Rates in Blacks
As noted by Dr. Joshua Muscat:
Despite suggestion of effect, none of the
studies conducted thus far have implicated
mentholated cigarettes as a materially
important cause of cancer
Our early study did show an increase in
esophageal CA in women
Most of the studies are hospital-based; Many
of them (e.g., by Stellman, Kabat, Muscat,
Hebert, et al.) use the same (AHF) dataset
Generally Null Results in These Studies Have
Not Resolved the Issue Definitively!
Why?
The lack of representativeness of Blacks in study
populations
The inability to define menthol cigarette
exposure unambiguously
The lack of data on potential effect-modifiers;
e.g., dietary factors, thermal damage from hot
beverages
Hebert JR, Kabat GC. Menthol cigarette smoking and Oesophageal cancer: results of a casecontrol study. Int J Epidemiol 1989;18:37-44.
The Picture in SC
Total Area: 31,113 mi2
Total Population: ~4.2m
Proportion AA: 31%
>40% of rural population is AA
SCCE in South Carolina
 Incidence among AA men is 7.63 times that
observed in EA men (vs. the US national
differential of ~ 4)
 The tobacco use rate in AAs is about 2/3 that of
EAs
1. Hebert JR. Invited commentary: menthol cigarettes and risk of lung cancer. Am J Epidemiol
2003;158(7):617-20.
2. Hebert JR, Adams SA, Daguise VG, Hurley D, Smith EW, Purdon C, Lawson A, Mitas M,
Reed CE. Esophageal cancer disparities in South Carolina: Early detection, special
programs, and descriptive epidemiology. J South Carolina Med Assoc 2006;102:201-9.
Histologic Type of Esophageal Cancer by Race; SC 1997-2002
10
Squamous Cell Carcinoma
Adenocarcinoma
9
Age-Adjusted Incidence Rates per 100,000
8
7
6
5
4
3
2
1
0
White
Black
All Races
South Carolina County-by-State Comparison of Black vs. White Incidence Rates of
Squamous Cell Esophageal Cancer (age-adjusted 1997-2002 Male incidence)
How Could Menthol Explain these
Differences (thinking circa 1988)?
Pyrollized menthol could exert a direct
carcinogenic effect
Anesthetic properties could lead to changes in
smoking behavior
Anesthetic properties may allow smokers to
consume beverages at a higher temperature
Menthol may modify specific nutrient effects
1. Hebert JR. Differences in biological responses to cigarette smoking remain unexplained. Am
J Pub Health 1991; 81:1679-1680.
2. Hebert JR, Kabat GC. Menthol cigarette smoking and oesophageal cancer: Results of a
case-control study. Int J Epidemiol 1989; 18:37-44.
Direct Action of Menthol
Under Fire
 Despite that menthol might be able to pyrolyze during smoking, there is no good
evidence that the normal process of smoking in humans actually results in
increased concentration of carcinogens or pro-carcinogens
 Problem: conventional view confuses/equates pyrolysis of menthol (whose
products do not appear to function as materially relevant carcinogens) with
increases in exposure to known carcinogens [which does appear to occur when
(esophageal) membrane is exposed simultaneously to NNK or B[a]P and
menthol (or menthol + EtOH)]
References:
Werley MS, Coggins CRE, Lee PN. Possible effects on smokers of cigarette mentholation: a review of
the evidence relating to key research questions. Regulatory Toxicol Pharmacol 2007;47(2):189-203.
Hébert, R., 2004. What’s new in “Nicotine & Tobacco Research?” Nicotine Tobacco Res. 6, S1–S4.
Menthol as a Penetrant
l-menthol and other substituted terpenes, such as
thiomenthol, enhance dermal absorption of
pharmaceutical agents; so, menthol, alone or in
combination with EtOH, may modify permeability
and solubility of tobacco carcinogens
References:
Werley MS, Coggins CRE, Lee PN. Possible effects on smokers of cigarette mentholation: a review of the
evidence relating to key research questions. Regulatory Toxicol Pharmacol 2007;47(2):189-203.
Azzi C, Zhang J, Purdon CH, Chapman JM, Nitcheva D, Hebert JR, Smith EW. Permeation and reservoir
formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BAP)
across porcine esophageal tissue in the presence of ethanol and menthol. Carcinogenesis
2006;27(1):137-45.
Static Franz cell for testing
esophageal permeation
Confocal Results
200µm
Histological staining, showing BAP presence
(green) in esophageal tissue, blue
fluorescence indicates nuclei, and red
demarcates smooth muscle cells below the
basal mucosal layer
20µm
Control (untreated
esophagus)
showing (red)
autofluorescence
20µm
BAP-exposed membrane (at 6h)
showing the foci of fluorescence
(green) due to carcinogen
reservoir formation
20µm
Perinuclear localization of the BAP
(green), closely associating with squamous
cell nuclei (blue)
Lung Cancer & Menthol
In an invited commentary on the Brooks et al. 2003 article
on lung cancer1 to which Dr. Muscat refers, I concluded
that “it is becoming clear that if there is an elevation in risk
of lung cancer from smoking mentholated cigarettes beyond
that from smoking regular, filter-tipped brands, it is either
subtle or refractory to the methods we have used thus far.”2
References
1. Brooks DR, Palmer JR, Strom BL, Rosenberg L. Menthol cigarettes and risk of lung cancer. Am J
Epidemiol 2003;158:609-16.
2. Hebert JR. Invited commentary: menthol cigarettes and risk of lung cancer. Am J Epidemiol
2003;158(7):617-20.
Considering Actions of
Menthol
 Epidemiology is concerned with both space and time, raising the issue
of simultaneous exposures
 It is recognized that cigarette-derived exposures represent mixtures that
are very complex
 Our results, which focus on menthol and well-known carcinogens, are
consistent with menthol acting in combination with NNK and B[a]P to
elevate risk – but only in situations where exposures happen in
combination; and this would be expected to be much more likely in the
esophagus than in the lungs
 More recent work, focusing on mucin, indicate > permeation than the
combination (of menthol and tobacco carcinogens) in a simple aqueous
solution (findings under review)
What Else Do We Know
About Menthol?
 Although there may be an effect on the function of cold receptors,
with cooling affecting airflow, there is no good evidence that
menthol increases overall tobacco exposure through an effect
such as modifying air passageways, patterns of inhalation, puff
volume, etc.
 Effects on physiology, if any, appear to be subtle and small;
however, the effect on solubility, membrane permeability, and
access to cellular machinery (e.g., nuclear DNA) appear to be
large and the largest of these is observed in the upper digestive
portion of the aerodigestive tract; i.e. the proximal esophagus
(because this is where the mixtures would tend to be the richest)
What else to consider?
 We already know that some of these cancers,
especially SCCE, evince strong effect modification
by other factors (lung cancer much less so)
 Menthol may modify nicotine/ carcinogen
metabolism
 In relation to menthol, 2nd-hand smoke is a non-issue
– exposures are too small to create very dangerous
mixtures
 Explore the possibility of subsets of susceptible of
individuals (adding to a line of research that began
>30 years ago)
Where to go?
 Large, and in some instances (e.g., for SCCE)
huge, racial disparities in rates of cancers of the
upper aerodigestive tract remain unexplained
 Even though it is a rare cancer, it makes sense to
focus on SCCE, as it is deadly (MIR>0.90),
much more common in Blacks, and is the place
where we would expect to see the most mixing
(i.e., menthol with tobacco carcinogens)
Thanks to the Many People and Institutions
that have influenced my thinking, especially
University of Washington
• Cole P. Dodge (UNICEF)
• Ross Prentice (FHCRC)
Harvard University
• Glorian Sorensen (DFCC)
• Karen Peterson (U Michigan)
• Mohamed el Lozy
• Walter Willett
• Larry Kushi (Kaiser P.)
Bombay University – Healis
• Prakash C. Gupta
Boston University – Bedford VA
• Donald Miller
Tata Memorial Centre
• Rajiv Sarin
American Health Foundation
• Ernst Wynder (deceased)
• Geoffrey Kabat (AECOM)
University of Massachusetts
• Ira Ockene (Prev Cardiology)
• Judy Ockene (Prev & Behav Med)
University of South Carolina
• John Ureda (Insights Consulting)
• Tom Hurley (EPID-BIOS)
• Bill Hrushesky (Dorn VA)
• Jane Teas (CCUSC)
• Harris Pastides (EPID-BIOS)
• John Vena (UGA)
• CPCP Junior Faculty